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Determining the Role of Plastin-3 in Osteoblast Differentiation and Mineralization

确定 Plastin-3 在成骨细胞分化和矿化中的作用

基本信息

批准号：
10671510
负责人：
Samantha Meagan Chin
金额：
$ 5.27万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671510
关键词：
2 year old Actins Adult Affect Alkaline Phosphatase Biochemical Biological Models Biology Bone Density Bone Development Bone Diseases Bone Resorption Bundling Calcium Cellular biology Child Childhood Clinical Collagen Diseases Cytoskeleton Defect Development Diagnosis Disease Elderly F-Actin Fishes Fracture Functional disorder Future Genes Genetic study Goals In Vitro Individual Institution Knock-in Life Link Mediating Medical Mentorship Modeling Molecular Mus Musculoskeletal Mutation Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Osteoporotic Pathogenicity Pathway interactions Patients Physicians Physiologic calcification Physiological Process Proteins Recording of previous events Recurrence Regulation Research Research Personnel Role Scientist Structure Techniques Testing Therapeutic Time Training Training Programs Transgenic Organisms Undifferentiated Universities Washington Zebrafish age related bone bone fragility bone health bone loss bone mass bone turnover early onset effective therapy experimental study genetic analysis in vivo in vivo Model insight knock-down mineralization multidisciplinary mutant new therapeutic target novel osteoblast differentiation osteogenic plastin response side effect skills therapeutic target transcriptome sequencing treatment response

项目摘要

Samantha Chin (PD/PI) PROJECT SUMMARY/ABSTRACT Osteoporosis is the most common bone disorder in the world and represents a significant clinical and societal burden due to related bone fractures. Although classically viewed as an age-related disorder, osteoporosis now more commonly describes a general condition of low bone mineral density that can arise in children as well as adults. The mainstay of osteoporosis treatment is anti-resorptive therapy, which seeks to curb bone resorption. This approach, however, is plagued by undesirable side-effects and concerns regarding long- term efficacy, particularly in children, underscoring the pressing need for alternative therapeutic targets and strategies to effectively treat osteoporosis. Plastin-3 (PLS3) is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis; however, the underlying pathophysiology is completely unknown. This is due in part to the fact that the role of PLS3 in bone health remains to be identified. This proposal will address these questions and build a basis to develop PLS3 as a novel anabolic anti-osteoporosis target. Genetic studies in mouse and zebrafish models suggest that PLS3 plays a role in osteoblast-mediated bone formation; however, it remains unclear how PLS3 mechanistically contributes to these processes. Aim 1 will employ pathogenic PLS3 mutants that are defective in either actin-bundling or calcium-regulation to elucidate how PLS3 promotes osteoblast differentiation and mineralization in cultured osteoblasts. In addition, RNA-seq analysis will also be used to identify novel pathways that contribute to mineralization in order to provide insight to the specific role of PLS3 and actin dynamics in osteoblast mineralization. To better understand how PLS3 contributes to regulation of bone development in vivo, Aim 2 is focused on developing a zebrafish model system to study the effect of pathogenic PLS3 mutations on bone formation. Taken together, this proposal will fill major gaps in our understanding of how PLS3 and its regulation of actin cytoskeleton dynamics contribute to bone health and the development of osteoporosis. The applicant has assembled a multi-disciplinary mentorship team with experts in the actin cytoskeleton, bone biology, cell biology, and zebrafish model systems that will support the applicant in completion of these aims. The proposal also takes advantage of the Washington University’s strengths in musculoskeletal and zebrafish research including the institution’s cutting-edge cores and facilities. Additionally, Washington University Medical Scientist Training Program has a rich history of supporting physician scientists at various stages of training that will also be invaluable to the applicant’s development. This training and mentorship will provide the applicant critical skills that will facilitate the transition to independent researcher and physician-scientist.

钱慧珊（PD/PI）